Every year in the United States at least 300,000 persons have strokes, 50,000 persons have leg amputations for ischemia, 100,000 persons have interventional procedures to treat leg ischemia, and as many as 5 percent of the population over age 60 have claudication, all caused by atherosclerotic peripheral arterial disease (PAD). Few studies of progression of PAD have been performed and none have used objective methods to evaluate disease progression in a large number of symptomatic subjects. Elevation of plasma homocysteine (HC) has been shown in multiple studies to be an independent risk factor for atherosclerotic vascular disease. The Homocysteine and Progression of Atherosclerosis Study (HPAS) is a long term prospective blinded mulitfactoral clinical study which began in 1991 to study the relationship between elevated plasma HC as well as other risk factors and PAD progression. Progression of disease in HPAS is evaluated by primary endpoints of death from vascular disease, and ankle brachial pressure index and carotid artery stenosis, both determined in the noninvasive vascular laboratory, and by secondary endpoints including stroke, myocardial infarction, need for vascular surgery, amputation, and other clinical events. The study is divided into two phases, conducted sequentially upon 400 patients with symptomatic lower extremity (LED) and cerebrovascular disease (CVD). The first phase was a three year natural history study in which progression of PAD has been shown to be significantly more likely in patients with elevated plasma HC. This phase currently has 344 patients and is nearing completion. This proposal requests support to continue the second phase of HPAS, a blinded prospective randomized placebo controlled trial of folic acid treatment in the same patient population. Folic acid treatment has been demonstrated to result in lowering of elevated plasma HC. The treatment trial addresses the clincial question: Do patients with symptomatic PAD treated with folate have less frequent/rapid progression of PAD than patients with symptomatic PAD treated with placebo? Completion of this study is of obvious major clinical importance. Elevated plasma HC is well established as an independent risk factor for both presence of and progression of atherosclerosis. If folate treatment results in less frequent/rapid progression of PAD, then it will be confirmed as the first effective treatment for atherosclerosis which is without toxic side effects and does not involve major changes in life/dietary habits. The HPAS study already underway is the only currently extant clinical research trial with sufficient power and adequate multifactoral design to objectively determine the role of treatment of elevated plasma HC on PAD progression.